Dr. Airie Kim is a Pulmonary and Critical Care physician who is greatly interested in the pathophysiology of sepsis and overwhelming inflammation in intensive care units (ICUs). One facet of this problem that is particularly amenable to laboratory study is anemia of inflammation (AI), a prevalent condition with strongly associated morbidities and mortality. Her long-term goal is to become an expert and academic leader in the field of AI, and eventually in other inflammation-related aspects of critical illness She will be supported by her primary mentor, Dr. Tomas Ganz, a leader in the field of anemia and iron metabolism, as well as her co- mentors and advisors who will provide their multidisciplinary expertise in training Dr. Kim in the theoretical and technical aspects of hematopoiesis and inflammation. Through UCLA's Clinical and Translational Science Institute (CTSI), Dr. Kim will have access to numerous career development seminars that address such topics as grant writing, manuscript preparation, and ethical research. She will also take graduate courses to obtain further training in immunology, pharmacology, hematopoiesis, and biostatistics. Dr. Kim is fortunate to have the full support of her institution, as well as the man advantages of carrying out her research project at UCLA, a renowned research center. This proposal outlines a 5-year research and career development plan that will prepare Dr. Kim to become an independent physician-scientist engaged in high-level scientific research. This project aims to elucidate the mechanisms of acute and severe AI, and to test novel therapies and their mechanisms of action in a mouse model. Dr. Kim recently characterized a mouse model of AI induced by heat-killed Brucella abortus (BA) that mimics the characteristics of human ICU anemia, including rapid onset, hypoferremia despite preserved iron stores, shortened erythrocyte lifespan, and depressed erythropoiesis. Using the BA mouse model of AI, Specific Aim 1a seeks to comprehensively investigate the underlying mechanisms, including potential contributions of reduced erythropoietin (EPO) production, decreased EPO receptor activity, and altered erythropoietic differentiation. One specific inflammatory cytokine that has been implicated in the development of AI is interferon-? (IFN-?). Using IFN-?R1-/- mice, Specific Aim 1b seeks to examine the mechanisms of IFN-? involvement in erythroid progenitor differentiation, macrophage activation, and erythrocyte lifespan. Two promising candidates for the treatment of AI are an orally bioavailable prolyl-hydroxylase (PHD) inhibitor that has been shown to improve anemia in patients with chronic renal failure, and erythroferrone (ERFE), a hormone newly identified by Dr. Kim's group that is induced by EPO and suppresses hepcidin expression. For Specific Aim 2a, Dr. Kim will test the PHD inhibitor in the BA mouse model in order to investigate its mechanistic and potential therapeutic effects in acute and severe inflammatory anemia. For Specific Aim 2b, Dr. Kim will use murine recombinant ERFE in the BA mouse model in order to investigate the effects on erythropoiesis and recovery in acute and severe AI. This project seeks to answer important mechanistic questions about AI, and investigate the use of novel therapies. With this work, Dr. Kim aims to advance our knowledge and potential treatments of the common but poorly understood condition of ICU anemia.